Retroviruses exhibit a wealth of evolutionary phenomena, including the ability to undergo rapid genetic change in response to varying selective pressure;the ability to vary in the use of host cell receptors;and the ability to become integrated in the genome of their host species and passed down through the generations as endogenous proviruses. In the prior project period, we have studied all these aspects of retrovirus evolution: We have looked at the mechanism of evolution of env genes by analyzing an unusual mutant that extends the host range of ALV beyond chicken, to quail, dog, and even human cells. We have isolated and studied an unusual mouse endogenous provirus that appears to occupy a special phylogenetic location between mouse and non mouse species. We have extensively analyzed the coevolution of humans and their endogenous proviruses, particulary the relatively recently inserted HERV-K family. We have developed sophisticated mathematical models for the evolution of replicating virus populations, describing the effects of mutation, selection, drift, linkage, and recombination on the accumulation (or loss) of deleterious mutations. Future work will address the following aims. 1. How do retroviral envelope genes evolve to use new receptors and to alter other important properties? We will use our extended host range mutants to test specific hypotheses for this process. 2. What are the functional and pathogenic properties of human endogenous retroviruses, particularly HERV-K? Can we isolate infectious virus? Is their expression or reintegration associated with malignancy? 3. How do important the forces of mutation, selection, recombination, and drift combine to direct retrovirus evolution? We will combine mathematical and in vitro modelling of virus replication to test specific evolutionary models. Relevance: In addition to its inestimable value as a tool of basic discovery, retrovirus evolution has important consequences for public health. In recent history, several retroviruses have evolved to use humans as hosts, with devastating consequences. Furthermore, evolution of viruses within a given host can have important consequences, such as use of different receptors, increased virulence, or resistance to drugs. Understanding of both how this evolution has occurred in our past and how it occurs in simple models will leave us better prepared to deal with such events as they happen.